NM_001754.5:c.59-46762T>C

Variant names:

• chr21-34939725-A-G
• rs1892687
• NM_001754.5:c.59-46762T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001754.5(RUNX1):​c.59-46762T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.582 in 152,116 control chromosomes in the GnomAD database, including 26,634 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.58 (26634 hom., cov: 32)
• Consequence: RUNX1 NM_001754.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.314
• Publications: 7 publications found

Genes affected

RUNX1 (HGNC:10471): (RUNX family transcription factor 1) Core binding factor (CBF) is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters. The protein encoded by this gene represents the alpha subunit of CBF and is thought to be involved in the development of normal hematopoiesis. Chromosomal translocations involving this gene are well-documented and have been associated with several types of leukemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

RUNX1 Gene-Disease associations (from GenCC):

• hereditary thrombocytopenia and hematologic cancer predisposition syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.734 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001754.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.59-46762T>C		intron	N/A	NP_001745.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.59-46762T>C		intron	N/A	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.59-46762T>C		intron	N/A	ENSP00000300305.3
	RUNX1	ENST00000416754.1	TSL:1	c.59-46762T>C		intron	N/A	ENSP00000405158.1

Frequencies

GnomAD3 genomes AF: 0.582 AC: 88476 AN: 151998 Hom.: 26589 Cov.: 32

Gnomad AFR AF: 0.741

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.464

Gnomad EAS AF: 0.707

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.510

Gnomad OTH AF: 0.567

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.582 AC: 88576 AN: 152116 Hom.: 26634 Cov.: 32 AF XY: 0.584 AC XY: 43419 AN XY: 74368

African (AFR) AF: 0.741 AC: 30753 AN: 41502

American (AMR) AF: 0.490 AC: 7495 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 1609 AN: 3468

East Asian (EAS) AF: 0.708 AC: 3666 AN: 5176

South Asian (SAS) AF: 0.542 AC: 2613 AN: 4824

European-Finnish (FIN) AF: 0.575 AC: 6072 AN: 10562

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.510 AC: 34702 AN: 67984

Other (OTH) AF: 0.565 AC: 1191 AN: 2108

Alfa AF: 0.547 Hom.: 4814

Bravo AF: 0.582

Asia WGS AF: 0.579 AC: 2009 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.61
PhyloP100		-0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1892687; hg19: chr21-36312022;